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Abstract

Background: Therapy
related myeloid neoplasms (t-MN) occur due to direct mutational events
of chemotherapeutic agents and radiotherapy. Disease latency,
mutational events and prognosis vary with drugs categories.Methods:
We describe a cohort of 30 patients, 18 females and 12 males, with
median age of 52.5 years (range, 20 to 64), submitted to allogeneic
stem cell transplantation (HSCT) in our department between September
1999 and March 2017. Patients had a history of solid tumour in 14
cases, haematological disease in 15 cases and both of them in one case.
After a median of 36.5 months (range, 4 to 190) from first neoplasm,
patients developed t-AML in 19 cases and t-MDS in 11 cases. Molecular
abnormalities were detected in 5 patients, while karyotype aberrations
were found in 17 patients. Patients received conventional chemotherapy
in 14 cases, azacitidine in 10 cases and both of them in one case. Five
patients were submitted to HSCT without previous treatment except for
supportive therapy. Results:
Seventeen patients obtained sustained CR after SCT, while 8 patients
showed resistant or relapsed disease. The remaining five patients died
early after SCT. At follow up time (May 2017) 13 patients were alive
with a median OS of 48 months (range 3-195), while 17 patients died
after a median of 4 months (range 1-27) by relapse mortality in 6 cases
and non-relapse mortality in the other 11 patients.Conclusions: Global OS was 43%. After SCT, 72.2% of patients with t-MN maintained a sustained CR.

Introduction

Therapy-related
myeloid neoplasms are recognized as a separate entity in the World
Health Organization (WHO) classification of haematological diseases.[1]
The incidence of therapy-related myeloid neoplasms (t-MN) continue to
rise due to the relative prolongation of survival and cure related to
chemo- and radio-therapy for primary malignancies, mostly breast cancer
and lymphoproliferative diseases.[2-7]The peak occurrence time of
therapy-related acute myeloid leukemia/myelodysplastic syndrome is 3 to
5 years after prior cytotoxic treatment, while the risk decreases
markedly after the first decade.[8] At present, t-MN account for 10–20%
of all malignant myeloid diseases.[9] Factors associated with an
increased risk of t-MN include exposure to alkylating agents,
topoisomerase II inhibitors, radiation therapy,[10-15] and older age at
treatment, in addition to genetic susceptibility.[16-21] t-MN after
anthracyclines and/or topoisomerase II inhibitors are associated with
occurrence of MLL translocation at 11q23 or RUNX1/AML1 at 21q22 after a
median latency of 1 to 3 years without a prodromal phase. t-MN after
alkylating agents have a median latency of 4 to 10 years and are often
preceded by myelodysplasia. It is associated with unbalanced chromosome
5 and 7 abnormalities, complex karyotypes, and/or TP53 mutations. After
radiation treatment, the highest risk for t-MN occurrence is registered
at 2 years and appears to normalize after 10 to 15 years.[22-24]
Particularly, patients who received radiation to chest, pelvis and
vertebrae for stomach, colorectal, liver, breast, endometrial,
prostate, and kidney cancers seem to be at a significantly higher risk
of developing t-MN.[24,25] More recently, it came to light the
potential role of various germline genetic factors in an individual’s
susceptibility to t-MN, particularly for those variants that alter drug
metabolism such as gene NQ01, glutathione-S-transferase,[9,18,19,26] as
well as those involved in DNA repair pathway such as BRCA, TP53 and
MDM2.[20,21]Clonal cytogenetic abnormalities are found in 75–90%
of t-MN, and 46-70% of them are adverse karyotype including complex
karyotype, deletion or loss of chromosome 5 and/or 7.[3,4] Cytogenetics
assessment is the principal prognostic factor for relapse rate and
overall survival (OS).[27-29] The heterogeneous treatments of
therapy-related myeloid neoplasms, ranging from best supportive care to
intensive chemotherapy, hypomethylating agents, and allogeneic stem
cell transplantation, do not allow definite conclusions on the best
treatment choice, particularly for elderly patients.[30,31] Treatment
of t-MN with conventional therapy is associated with a poor outcome in
terms of survival (6 months),[8,32] remission rate (28% to 50%) and
duration of the remission.[33-35] On the other hand, conventional
chemotherapy might be a reasonable option for t-MN with favourable
karyotype such as inv(16), t(16;16), t(15;17) or t(8;21), since the
reported remission rate and the disease free survival are similar to
those seen for the de novo counterpart.[35,36] The introduction of new
drugs such as azacitidine and decitabine has shown promising results in
the management of t-MN with an acceptable toxicity profile also for
frail patients, and with an overall response rate of approximately
40%.[4,30,31,37-44]

Allogeneic Stem Cell Transplantation for t-MN

Allogeneic
haematopoietic stem cell transplantation (HSCT) represents the only
potentially curative strategy, but it is not feasible for all patients
due to age, comorbidities in elderly patients, poor organ reserve and
high non-relapse mortality (NRM).[4,45] The haematopoietic cell
transplantation-specific comorbidity index (HCT-CI) was developed as a
sensitive tool to measure the burden of comorbidities before HSCT and
to predict both the risks of NRM and the probabilities of survival
after HSCT.[46] As reported by ElSawy et al.[47] in the HCT-CI
validation study, the three HCT-CI risk groups with score 0, 1–2, and
≥3 result in a NRM of 14%, 23%, and 39% with a survival of 74%, 61%,
and 39%, respectively. Therefore, HSCT should be offer as a reliable
option to fit patients with good performance status, intermediate and
poor risk karyotype with suitable and available donor.[9,27,28,48-50]
With particularly interest to t-MN, the Center of International Bone
Marrow Transplantation Research (CIBMTR) and the European Group for
Bone and Marrow Transplantation (EBMT) extrapolated pre-transplant
factors predicting post-HSCT outcome in these patients from larges
study cohorts. CIBMTR conducted a large study cohorts on t-MN and
proposed a prediction model of survival after allogeneic HSCT using the
following four risk factors: age older than 35 years, poor-risk
cytogenetics, t-AML not in remission or advanced t-MDS, donor other
than an HLA-identical sibling or a partially or well-matched unrelated
donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of
these risk factors was 50%, 26%, 21%, 10%, and 4%, respectively.[27]
Also the EBMT group[28] reported that disease stage at transplant
different from complete remission, abnormal cytogenetics (excluding
t(8;21), inv(16) and t(15;17)) and patients’ age >40 years are the
most significant factors predicting survival, relapse rate,
disease-free survival (DFS) and NRM dividing patients into three risk
groups: low, intermediate and high. Overall survival for the
above-mentioned groups was 62%, 33% and 24%, respectively; DFS was 58%
(low), 32% (intermediate) and 20% (high); NRM was 22% (low), 37%
(intermediate) and 38% (high); finally, relapse rate was 20% (low), 31%
(intermediate) and 32% (high) respectively. We performed a
review of the literature on therapy-related AML/MDS submitted to
allogeneic stem cell transplantation excluding AML secondary to MDS
progression. Detailed results concerning cohort size, median follow up,
overall survival, NRM incidence, and relapse rate are depicted in Table 1.
The reported outcomes for patients submitted to HSCT for
therapy-related AML/MDS are very heterogeneous. Median OS ranges from
22% to 66%, with a NRM of 21 to 58% and a relapse rate of 26% to
42%.[2,27,28,38,51-62]

Table
1. Results of the review: outcomes of patients with therapy-related AML/MDS submitted to HSCT.

Monocentric Observational Study

Patients and disease characteristics.
We retrospectively analyzed patients submitted to HSCT in our
department and identified 30 patients with a diagnosis of
therapy-related myeloid neoplasm (t-MN) transplanted between September
1999 and March 2017. Patients were 18 females (60%) and 12 males (40%)
with a median age of 52.5 years (range, 20 to 64). Secondary neoplasm
was acute myeloid leukemia (t-AML) in 19 cases (63%) and myelodysplasia
(t-MDS) in 11 cases (37%). Data were collected through retrospective
chart review and after institutional review board approval. The median
time occurred from primary disease to t-MN occurrence was of 36.5
months (range, 4 to 190). Primary disease was hematologic in 15 cases
(50%): Hodgkin’s disease (n=2), non-Hodgkin’s lymphoma (n=9), acute
lymphoblastic leukemia (n=1), chronic lymphocytic leukemia (n=2) and
acute myeloid leukemia (n=1). Fourteen patients (50%) had a previous
diagnosis of solid tumor: medulloblastoma (n=1), breast (n=8), Ewing
sarcoma (n=1), thyroid (n=1), bladder (n=2) and vagina/anus (n=1). One
patient had a history of both haematological (non-Hodgkin's lymphoma)
and solid tumor (breast). Twelve patients (40%) had been previously
treated with chemotherapy, 8 patients (26.7%) with chemotherapy and
autologous transplantation, 2 (6.7%) patients with radiotherapy, one
patient (3.3%) with radioiodine therapy and 7 patients (23.3%) with a
combination of chemo- and radiotherapy. At t-MN diagnosis all patients
had received a median of 2 lines of therapy (range, 1 to 6) for their
primary malignancy. All patients were free of their primary
malignancies at the time of transplantation.Revised International
Prognostic Scoring System (IPSS-R)[63] was used to classify
cytogenetics of t-MDS, while European Leukemia Net AML risk
stratification by cytogenetics was used for AML.[64] Karyotype was
available for 28 out of 30 patients. Eleven patients (36.7%) had normal
karyotype, three patients (10%) had a favourable karyotype, 5 patients
(16.7%) had an intermediate-risk karyotype and 9 patients (30%) had an
adverse-risk karyotype. Molecular cytogenetics analyses were available
for 14 out of 30 patients: FLT3/ITD+ (n=2), CBFB/MYH11 (n=1), NPM1+
(n=1), NPM1 and FLT3/ITD double positivity (n=1), no abnormalities
(n=9). A detailed description of primary neoplasms, treatment for
primary neoplasm and t-HN is reported in Table 2. Transplant features and outcomes are depicted in Table 3.

Statistical analysis.
Overall survival and disease-free survival (DFS) were estimated using
Kaplan-Meier product method, while for curves comparison log-rank test
was applied. χ2 test and Fisher’s exact test were used to assess
associations between categorical variables and OS, NRM, RRD, DFS. A
competing risk analysis was performed to calculate the cumulative
incidence of relapse-related death (RRD) and non-relapse mortality
(NRM). For NRM, relapse was the competing event, and for relapse, NRM
was the competing event. Fine and Gray’s method for cumulative
incidence of RRD and NRM were used to compare different groups.
Statistical analysis was realized using NCSS 10. A p-value ≤ 0.05 was
considered statistically significant.

Results

Engraftment and GvHD. White blood cells count of ≥1.0x109/L and stable platelets count ≥20.0x109/L
were reached at median day +21 (range, 11 to 130) and median day +15
(range, 10 to 45), respectively. Three patients died early before
achieving stable engraftment. Acute GvHD (aGvHD)[65] occurred in
15 patients (50%) and global grading was as follows: grade I (n=3),
grade II (n=5), grade III (n=6), and grade IV (n=1). Among them, three
patients died because of aGvHD. Chronic GvHD (cGvHD)[66] was diagnosed in
14 out of 23 patients surviving after day +100 (65%) and global scoring
was as follows: mild (n=3), moderate (n=7) and severe (n=4). One of
them died for cGvHD-related complications. Response.
Morphological bone marrow cytology was performed on day +30 after HSCT
only in 25 patients because of early death in the others five. Three
patients (12%) had a persistence of the underlying disease, whereas
twenty-two patients achieved a CR (88%) on day +30. Among them, 5
patients (22.7%) experienced a relapse after a median time of 6 months
(range, 3 to 15), while 17 patients (77.3%) maintained a CR after a
median time of 27 months (range, 3 to 195). Median 2-ys DFS after HSCT
was of 72.2% (95% CI 51.1 to 93.3) (Figure 1A). Overall survival, NRM and RRD.
At the follow up data fixed on May 2017, 13 patients were alive after a
median time of 48 months (range, 3 to 195), while 17 patients died
after a median time of 4 months (range, 1 to 27). The causes of death
were as follows: underlying disease (n=6), GvHD (n=3), EBV-related
post-transplant lymphoproliferative disease (PTLD) (n=1) and infectious
complications (n=7). The overall survival at 2 years after HSCT was of
40.5% (95% CI 22.1 to 58.9), whereas the cumulative incidence of NRM
and RRD at 2 years was of 44.4% (95% CI 27.6 to 71.2) and 29.6% (95% CI
15 to 58.6), respectively (Figures 1B, 1C and 1D).
No differences in terms of OS, NRM, RRD and DFS were seen stratifying
patients according to underlying disease, disease status at transplant,
previous treatment received, karyotype risk, patients and donor
characteristics, stem cell source. An association was identified
between OS and cGvHD development after HSCT, as well as between OS and
relapse occurrence. Overall survival was higher in the group with cGvHD
than those detected in the group without this complication (68% vs.
22%, p=0.018). Median OS was of 6 months (range, 4.6 to 7.4) in the
group without cGvHD, while it was not reached in the group with cGvHD
(p=0.0002, Figure 1E). An
higher mortality was recorded in the group of patients who experienced
a relapse of the underlying disease as compared with patients who did
not relapsed after HSCT (67% vs. 13%, p=0.011). Median OS in the group
relapsed after HSCT was of 5 months (range, 2.2 to 7.8) as compared to
patients without relapse, for whom a median OS was not reached
(p=0.004, Figure 1F).
Relatively to NRM, an association was identified with the conditioning
regimen: surprisingly, NRM was higher for patients who had received a
reduced intensity conditioning as compared to those who had received a
myeloablative one (p=0.046). Two-years cumulative incidence of NRM was
of 74% (95% CI 49 to 100) after RIC transplant and 24% (95% CI 10 to
58) after ABL transplant (p=0.022, Figure 1G).
Finally, also for RRD an association was found with cGvHD development
after HSCT: among patients with cGvHD, a minor number of RRD was
recorded as compared to patients who had not developed this
complication (p=0.018). The cumulative incidence of RRD at 2 years
after HSCT was of 9% (95% CI 1 to 59) for patients with cGvHD and 65%
(95% CI 38 to 100) for patients without cGvHD (p=0.004, Figure 1H).Two
patients (6.7%) experienced a third tumor, in particular a breast
cancer occurred thirteen years after HSCT and an EBV-related PTLD of
the brain occurred eight months after HSCT.

In
the last two decades, many authors published results concerning
different cohorts of patients with therapy-related acute myeloid
leukemia or myelodysplasia submitted to allogeneic stem cell
transplantation. An high heterogeneity in the percentage of OS (22% to
66%), NRM (21% to 58%) and relapse rate (26% to 42%) come to light from
these experience.[2,27,28,38,51-62] Each of these studies highlighted a
different key point in this transplant setting, which might affect
outcome after HSCT. The mainly predicting factor for OS resulted the
karyotype and the recipient performance status at transplant.[38,54,56]
Patients achieving a CR before transplantation showed better outcomes,
whereas multiple therapy lines increase organ damage as well as the
incidence of neutropenia, infection events and the immunosuppression of
the patient increase TRM.[54,60,61] Patients at risk for
treatment-related myeloid neoplasms should be followed closely and be
considered for stem-cell transplantation early in the course of
myelodysplasia.[38,58,61] Considering the incremented risk of relapse
according to blasts percentage, patients with secondary MDS should be
direct to transplantation before the progression into AML, and if
secondary AML occurs, they should be transplanted as soon as
possible.[61] For patients who did not achieved a CR pre-transplant,
rapid transplantation, also considering alternative donor, could offer
a reasonable outcome, reducing the risk of deterioration of the
patient’s performance status. OS after HSCT in patients aged 60 years
or above was very poor.[50,51,67,68] Reduced intensity conditioning and
conditioning with targeted busulphan dose[38,51,58] might reduce TRM,
especially for those patients with a reduced organ reserve. As reported
for patients with de novo MDS,[69] pre-transplant disease stage,
cytogenetic risk group,[57,56] type of therapy given for the original
disease, transplant conditioning regimen, and patient age[61]
significantly affect relapse-free survival among patients with
secondary MDS/t-AML.[38] Concerning to stem cell source, peripheral
blood instead of bone marrow appeared to reduce NRM38 and relapse
rate[38,57] and to improve OS.[38] On the other hand, controversial
data were reported relative to donor source impact on OS.[2,27,38,53,70]In
our cohort, global OS appeared to fit with those reported from several
authors (40.5% vs 22-66%), whereas NRM appeared the major cause of
death, even if the NRM rate was comparable to others data (44% vs
21-58%).[2,27,28,38,51-62] Surprisingly, we observed an high DFS
(72.2%) perhaps attributable to high cGvHD rate after HSCT,
corresponding to an enhanced GvL effect. In fact, among patients with
cGvHD a reduced RRD and an increased OS were registered. Graft-versus
leukemia (GvL) effect, especially associated with chronic GvHD,
improved DFS and OS also in adverse karyotype t-MN submitted to
HSCT.[71] Probably due to the small size of our study group, no
differences in terms of post-transplant outcomes emerged dividing
patients according to recipient age, previous treatment, disease status
at transplant, karyotype, donor or stem cell source. Unexpectedly, we
found a higher NRM among patients who had received a RIC transplant as
compared to ABL, but no differences in performance status,
pre-transplant risk score or disease status existed between the two
groups. An interesting feature revealed by our curves was that
DFS reached a plateau approximately after the first year post HSCT,
while OS reached its prolonged plateau after the second one. In fact,
no relapse was ascertained after the first year post-HSCT, so that
eighteen patients (56.7%) obtained and maintained a complete remission
after HSCT. On the other hand, no deaths were recorded after the second
year post-HSCT, with an OS of 40.5% at the follow up time.

Conclusions

The
incidence of t-MN is increasing as more individuals survive treatment
for a primary cancer diagnosis. At t-MN diagnosis,[72] physicians
should evaluate molecular and cytogenetic risk of the disease,
performance status, age and comorbidities of patients, and should start
HLA-typing to timely detect a suitable donor. Older patients with poor
performance status should be offered clinical trials or best supportive
care. For fit patients, molecular and cytogenetics stratification is
crucial. t-APL might benefit from standard first line protocols.
Favorable karyotype t-MN should be treated with standard induction
chemotherapy followed by high dose cytarabine consolidation course.
Normal karyotype t-MN could receive standard induction chemotherapy
followed by HSCT while poor molecular karyotype t-MN should be
encouraged to participate in prospective clinical trials specifically
designed and they should be considered early for allogeneic HCT.[51]
Upfront HSCT could be offered to patients with low blast count and poor
performance status.

The Mediterranean Journal of Hematology and Infectious Diseases [eISSN 2035-3006]is owned by the U.C.S.C. and it is published by Mattioli 1885, Fidenza, Italy.The MJHID is indexed and abstracted in Science Citation Index Expandedand Journal Citation Reports/InCites beginning with V. 7 (1) 2015.